Product Pharmacology and Medical Actives in Achieving Therapeutic Benefits

James R. Schwartz Beauty Care Product Development, The Procter & Gamble Company, Cincinnati, Ohio, USA

J Investig Dermatol Symp Proc 10:198 –200, 2005

Scalp skin is physiologically very similar to non-palmoplan- at least as strong a determinant of in-use activity as the tar skin of the rest of the body, except for the very high intrinsic active potency. For example, a comparison of clin- concentration of sebaceous glands (Giacometti, 1965). The ical flake-reduction efficacy of a variety 1% PTZ-based D/ scalp environment, however, is much different in being cov- SD shampoo products demonstrates a wide range of mag- ered by a thick fabric of hair. There are about 250 hair fibers nitude of therapeutic benefits. Much of this variation is likely per cm2, which results, for a typical individual, in a hair sur- due to the varying efficiency of delivery of PTZ, a particulate face area of 50,000 cm2 relative to the scalp surface area of active, to the scalp surface. Particulate PTZ delivery will be 600 cm2. Together, these parameters indicate the relative affected by the physical size and shape of the particle (as inaccessibility of the scalp surface to targeted delivery of well as other formulation parameters, which will not be cov- actives; relatively low delivery efficiency in this protected ered further here). Particles which are flat cover the scalp environment is an inherent challenge to achieving thera- surface more efficiently than those that are not. The particle peutic benefits. This is especially true of the most patient- size is also critical as smaller particles provide better surface friendly format—shampoos—since a rinsing step is involved coverage but are more difficult to retain on the scalp after and the product cannot interfere with achieving desired rinsing. These two opposing factors result in an optimum hair cosmetic benefits (compliance decreases dramatically size to maximize active delivery. Shampoo product formu- if hair cosmetics are poor). This places a large demand on lations utilizing PTZ particles optimized for delivery outper- actives with high activity since delivery efficiency will be form those utilizing standard forms of the active (Fig 1). This inherently low as well as development of product phar- exemplifies one variable, beyond active potency, that must macologies that maximize the benefit of the actives em- be considered in selecting a therapeutic treatment. ployed. This situation will be exemplified for the most Another important pharmacological variable that must be common scalp care therapeutic products, those designed considered is the role of the ‘‘non-functional’’ excipients in to treat dandruff and seborrheic dermatitis (D/SD) utilizing anti-fungal actives to reduce Malassezia content on the scalp. The most common anti-fungal materials used in D/SD scalp therapies include those based on rational chemical design principles (ketoconazole, climbazole, pyrithione zinc (PTZ), piroctone olamine and ciclopirox olamine) as well as materials originating from indeterminate histories (selenium sulfide, sulfur, coal tar, and salicylic acid). Because of the aforementioned demands on activity due to challenging delivery, only those materials with high intrinsic anti-fungal activity should be considered as the basis for therapeutic products. Based on measurement of minimal inhibitory concentrations (MIC) against Malassezia, the most potent materials from this group are pyrithione zinc, selenium sulfide, climbazole, and ketoconazole (VanGerven and Odds, 1995; Schmid and Ru¨ hl-Ho¨ rster, 1996). For a formulated therapeutic product to be effective, a Figure 1 potent active is a necessary but insufficient condition to The impact of pyrithione zinc (PTZ) particle size on clinically ob- achieve activity. The way the active is delivered to the scalp served anti-dandruff efficacy from shampoo matrices. Sub-micron from the product formula, i.e., the product pharmacology, is particles are difficult to retain on the scalp after rinsing, whereas the distribution of particles on the surface of the scalp (inset) improves as the particles become smaller (note fungal cell target drawn to scale). These off-setting factors result in an optimum particle size for efficacy Abbreviation: PTZ, pyrithione zinc of 2.5 mm.

Copyright r 2005 by The Society for Investigative Dermatology, Inc. 198 10 : 3 DECEMBER 2005 PRODUCT PHARMACOLOGY AND THERAPEUTIC BENEFITS 199

Figure 2 A summary of relevant pyrithione zinc (PTZ) equilibria governing realization of anti-fungal activity. (A) PTZ particles yield a soluble portion of PTZ molecules, which penetrate the fungal cell membrane (green). (B) PTZ undergoes dissociative equilibria, which reduce the portion of the material present in the bio-active complexed form. (C) The addition of an exogenous source of zinc ions (red) shifts the equilibria in the favor of the complexed PTZ form, thereby increasing delivery to the fungal cells (red).

the product formulation–it is well known that they can mod- 100 times more effective than, e.g., the iron salt (MIC of 500 ulate, either positively or negatively, the activity of the drug ppm). This clearly highlights the importance of zinc to the active. A specific example of how product excipients can activity of PTZ and establishes the intact PTZ material as affect the activity of a scalp care formula is the addition of the anti-fungal bio-active species. This conclusion becomes zinc materials to PTZ-based therapeutic products. To un- the basis for understanding the effect of the formulation derstand the mechanism behind this effect requires some containing a zinc excipient on the activity of PTZ. understanding of a key component of the anti-fungal mech- PTZ, like all metal-organic complexes when in a liquid anism of the active ingredient PTZ itself. medium, is governed by an equilibrium between the asso- Although the detailed understanding of the biological ciated zinc-pyrithione complex (i.e., PTZ) and dissociated mechanism of PTZ is beyond the scope of the article, it is zinc and pyrithione components (Seymour and Bailey, important to highlight the importance of the zinc component 1981). Since PTZ is the bio-active species, dissociation of the metal-organic complex PTZ. PTZ is based on the has negative consequences on efficacy. The greater the organic entity pyrithione (PT) where zinc ion ( þ 2) forms a dissociation, the less PTZ is present in the medium in a form salt with PT (1) in a 1:2 ratio. Evaluation of the in vitro anti- leading to anti-fungal activity. This is represented in the fungal activity of the organic component (sodium pyrithione) equilibria summarized in Fig 2. as well as a number of metal salts of this material (including Zinc ion has essentially no anti-fungal activity of its own, zinc, iron, nickel, and copper), demonstrates a range of over but enhances the anti-fungal activity of PTZ by over an or- three orders of magnitude (1000-fold) of potency. The zinc der of magnitude in in vitro evaluations (Fig 3). The mech- salt (MIC of 8 ppm) is almost 10 times more potent than anism involves shifting the equilibrium between PTZ and its sodium pyrithione (MIC of 64 ppm) alone and approximately dissociated components. The basis for this effect is the 200 SCHWARTZ JID SYMPOSIUM PROCEEDINGS

on increasing the bio-availability of PTZ as the equilibria in Fig 2C demonstrate. The zinc-enhanced PTZ activity observed in vitro and understood in terms of increased bio-availability results in increased performance in vivo in complex matrices as well. Quantitation of in vivo Malassezia reduction from shampoo matrices demonstrates PTZ formulation with zinc to be more effective than PTZ formulations alone. This benefit also translates to significantly improved clinical flake re- duction from shampoos containing added zinc as an ex- cipient. In summary, whereas potent scalp actives must be se- lected to achieve therapeutic activity, the product pharma- cology must be considered in both the design and selection of the product. Utilizing the example of PTZ-based D/SD treatments, wide variability in clinical performance has been observed. The origins can be understood in terms of how efficiently the product delivers the active to the scalp surface Figure 3 as well as the role that excipients play on modulating activity Kill rate microbiology evaluation of shampoo prototypes contain- of the product formulation containing the drug active. ing no active (placebo), pyrithione zinc (PTZ) alone, added zinc alone and the combination. Zinc alone has no activity, but it potenti- ates the activity of the PTZ formula. This work was funded by the Procter & Gamble Company. The author wishes to acknowledge David Kaufman for microbiological assess- ments and Durk Domaschko and Matt Chestnut for visualization of well-established principle in chemical equilibria called intracellular zinc delivery. LeChaˆ telier’s Principle. Briefly, it states that a change im- DOI: 10.1111/j.1087-0024.2005.10105.x posed on a system at equilibrium shifts the equilibrium in a way that reduces the effect of the change. In practical Manuscript received September 20, 2004; revised November 23, 2004; accepted for publication December 2, 2004 terms, this means that the addition of a material which ap- pears on one side of the equilibrium shifts the equilibrium in Address correspondence to: James R. Schwartz, PhD, The Procter & the opposite direction. In the case of the PTZ equilibria, Gamble Company, 11511 Reed Hartman Hwy, Cincinnati, OH 45241, added zinc forces the equilibrium towards the bio-active USA. Email: [email protected] PTZ complex. In effect, additional zinc is acting in the for- mula to increase the bio-availability of PTZ to exert its anti- fungal activity and is therefore considered a potentiated References PTZ formula. Giacometti L: The anatomy of the human scalp. Adv Biol Skin 6:107–120, 1965 Support for the mechanism comes from quantitation of Kim CH, Kim JH, Moon SJ, et al: Pyrithione, a zinc ionophore, inhibits NF-kB PTZ penetration into model mammalian cells. This can be activation. Biochem Biophys Res Commun 259:505–509, 1999 Schmid A, Ru¨ hl-Ho¨ rster B: In vitro susceptibility of Malassezia furfur. Arzneimittel monitored by evaluating zinc levels within cells (modeling Forschung 46:442–444, 1996 delivery to Malassezia yeast cells) using fluorescent tech- Seymour MD, Bailey DL: Thin-layer chromatography of pyrithiones. J Chromatog niques (Kim et al, 1999). Comparison of the zinc levels in 206:301–310, 1981 cells exposed to either PTZ or PTZ plus zinc, shows much VanGerven F, Odds FC: The anti-Malassezia fufur activity in vitro and in exper- imental dermatitis of six imidazole antifungal agents: Bifinazole, clot- higher levels of intracellular PTZ (as zinc) in the case of rimazole, flutrimazole, ketoconazole, miconazole and sertaconazole. added zinc. This is the result of the effect additional zinc has Mycoses 38:389–393, 1995